Nerlynx (neratinib)

P1/2, N=10, Terminated, M.D. Anderson Cancer Center | Trial completion date: Dec 2028 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2028 --> Nov 2024; Sponsor Withdrew Support

P1/2, N=10, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=47 --> 10

After receiving capecitabine, lapatinib, gonadotropin-releasing hormone (GnRH) agonist, and tamoxifen, multiple new lesions appeared in the brain after 14 months. The patient then received capecitabine, neratinib, GnRH agonist, and letrozole; however, her brain metastases still progressed after 7 months...Now aged 30, the patient is continuing to receive T-DXd treatment to prevent recurrence. We conclude that T-DXd was effective for the treatment of brain metastases in this young patient with triple-positive metastatic breast cancer who had multiple risk factors and had received several anti-HER2 therapies prior to T-DXd.

P2, N=315, Active, not recruiting, Spanish Breast Cancer Research Group | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2025 --> Oct 2024

P2, N=100, Active, not recruiting, Scott R. Plotkin, MD, PhD | Recruiting --> Active, not recruiting

P2, N=200, Not yet recruiting, Peking University Shenzhen Hospital

In contrast, anastrozole and letrozole show lower binding affinities for HER2 and EGFR due to their simpler structures but are potent aromatase inhibitors, making them effective in treating estrogen receptor-positive (ER-positive) breast cancers. In conclusion, DFT and molecular docking studies affirm the suitability of lapatinib, tucatinib, and neratinib for HER2-positive cancers, while anastrozole and letrozole are effective in ER-positive cancers, emphasizing the role of molecular structure and binding affinity in optimizing cancer treatment strategies.

By regulating intracellular and extracellular signaling pathways, TG2 promotes breast cancer metastasis to lung, brain, liver and bone, as well as resistance to various chemotherapy drugs including docetaxel, doxorubicin, platinum and neratinib. This review covers the extensive and rapidly growing field of the role of TG2 in breast cancer. Based on the role of TG2 in EMT, we summarize TG2-related signaling pathways in breast cancer metastasis and drug resistance and discuss TG2 as a therapeutic target.

P1, N=30, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1/2, N=83, Recruiting, Virginia Commonwealth University | Trial completion date: Dec 2025 --> May 2026 | Trial primary completion date: Dec 2024 --> May 2025

P1/2, N=14, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.

The SUMMIT trial demonstrated meaningful activity of neratinib + fulvestrant + trastuzumab in patients with HR+, HER2 non-amplified, HER2-mutant MBC. In patients with mILC and HER2 mutation, there was a trend toward longer TTP with T-DXd. Genomic data could aid in prognostication in patients with mILC treated with T-DXd. These findings warrant confirmation in larger cohorts.

These findings were consistent with those reported for SUMMIT hormone receptor-positive (HR+) HER2-mutant mBC cohorts, in which patients treated with N or N + fulvestrant (N+F) experienced promising clinical responses but shorter DOR. Although limited by small numbers, addition of T to N in patients with HER2-mutant mTNBC, despite deepening and prolonging response, did not appear to preclude eventual emergence of either on-pathway (ERBB3) or off-pathway (KRAS, TP53) mutations. In contrast to observations in N+F+T-treated patients with HR+, HER2-mutant disease, no additional HER2 alterations were detected upon progression in N+T-treated patients with mTNBC in this small dataset. Future investigations may evaluate clinical utility of sequencing therapies targeted to mutations acquired in response to N-based therapy in patients with HER2-mutant mTNBC.

P1, N=45, Recruiting, Virginia Commonwealth University | Trial primary completion date: Aug 2024 --> Aug 2026

To overcome these obstacles, we have engineered cyclic Arg-Gly-Asp (cRGD)-modified red blood cell membrane (RBCm)-coated multidrug nanocomplexes, which were self-assembled from the Polo-like kinase 1 siRNA (siPlk1) and an irreversible tyrosine kinase inhibitor neratinib targeted to human epidermal growth factor receptor 2 (HER2) overexpressed in breast cancer...The cRGD-modified red blood cell membranes coated on the surface of the multidrug nanoparticles could enhance drug stability in circulation and tumor accumulation. This targeted combinational therapy significantly enhanced the antitumor efficiency in HER2-positive breast cancer in vitro and in vivo.

P2, N=460, Recruiting, Patrick Wen, MD | Trial completion date: Dec 2025 --> Apr 2027 | Trial primary completion date: Mar 2025 --> Feb 2027

P2, N=22, Recruiting, University of Rochester | Trial completion date: Sep 2025 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2026

P2, N=48, Recruiting, Ruth O'Regan | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

In the liquid biopsies, we detected ESR1 mutations in 42 cases (25.9%) and ERBB2 mutations in six cases (3.7%), arguing for a change in therapy to fulvestrant, elacestrant, or neratinib. Furthermore, 17 cases had detectable TP53 mutations, associated with resistance against endocrine therapy. We conclude that liquid biopsy testing is a noninvasive, sensitive, and helpful method to optimize therapeutic decisions in metastatic BC.

P1, N=20, Recruiting, Baylor Research Institute | Not yet recruiting --> Recruiting | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

Several TKIs, including lapatinib, neratinib, and tucatinib, have been developed and are currently used in clinical settings, often in combination with chemotherapy, endocrine therapy, or other targeted agents. TKIs have emerged as a promising therapeutic option for patients with breast cancer and hold potential for treating other breast cancer subtypes. The development of new TKIs and their integration into personalized treatment strategies will continue to shape the future of breast cancer therapy.

Furthermore, when we tested Neratinib (an inhibitor of MAD2L1) and iMDK (an inhibitor of MDK) we found that they are effective on MPM cells, in part phenocopying the effects of MAD2L1 and MDK gene silencing. In summary, in the present work, we report that BAG2, MAD2L1, and MDK are bona fide cancer-driver genes for MPM worth of further studies.

Margetuximab plus chemotherapy was used as fourth- or later-line treatment in patients who had received multiple HER2-targeted agents, including trastuzumab, pertuzumab, ado-trastuzumab emtansine, trastuzumab deruxtecan, tucatinib, and neratinib. Patients responded to margetuximab plus chemotherapy with real-world progression-free survival (PFS) of 3, 4, and 7 months. Clinical outcomes from three heavily pretreated patients with metastatic HER2+/HR+ MBC demonstrated that margetuximab plus chemotherapy resulted in real-world PFS comparable to that reported in the controlled pivotal clinical trial and support use of this targeted therapy option in appropriately identified patients.

This study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.

Rat colons were markedly altered in appearance, with similar short circuit currents (Isc) and responses to carbachol and forskolin. Preclinical evidence supports an inflammatory component of neratinib-induced diarrhea without mucosal barrier function loss. Colonoscopy findings in patients with BC indicate mild or no pathological changes in the colon due to neratinib treatment.

The dosage form (marketed in the United States, China, Europe, and other regions) is a tablet for oral administration, and the brand product (NERLYNX) has patent protection for the crystalline neratinib maleate monohydrate form. This paper describes the product development using stable crystalline neratinib maleate anhydrous form, stability study, bioequivalence (BE) study of the products, and discussion of the adverse effects observed in the clinical study.

Patients are more likely to complete 1 year of adjuvant neratinib with dose up-titration. Dose reductions and interruptions did not affect neratinib adherence in our patient population. Seven patients (11%) in our study developed metastatic disease, all of whom did not complete adjuvant neratinib treatment.

Researchers have developed monoclonal antibodies like Trastuzumab and Pertuzumab against HER2 receptors, which have proven highly beneficial in cancer therapy. Bispecific antibodies like Zanidatamab and antibody-drug conjugates like T-DM1 have been developed to overcome the resistance associated with monotherapy. Small molecules such as Lapatinib, Neratinib, and Pyrotinib were initially developed for treating breast cancer...This comprehensive review covers the structural characteristics of HER2, the HER family signaling pathway mechanism, recent findings regarding HER2 receptor involvement in various cancers, and diverse HER2-targeted therapies. This information provides a comprehensive understanding of HER2-targeted strategies in the evolving field of cancer treatment.

Moreover, overexpression of FLAG-tagged PADI3 in BT474 cells provoked resistance to the antiproliferative action of neratinib. Together, these results uncover a role of PADI3 in the regulation of sensitivity to neratinib in breast cancer cells overexpressing HER2 and open the possibility of using PADI3 inhibitors to fight resistance to neratinib.

Currently, widely used clinical HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, have several drawbacks, including susceptibility to drug resistance caused by HER2 mutations and adverse effects from insufficient HER2 selectivity...Typically, SPH5030 has advanced to phase I clinical trials for its strong suppression of four HER2 mutations. This review discusses the latest research progress in HER2 TKIs, with a focus on the structural optimization process and structure-activity relationship analysis. In particular, this study highlights promising design strategies to address these challenges, providing insightful information and inspiration for future development in this field.

P2, N=60, Not yet recruiting, Convalife (Shanghai) Co., Ltd.

This study underscores the potential of ctDNA as a predictive and prognostic biomarker for patients with HER2-mutated advanced-stage solid tumors treated with neratinib and trastuzumab. The presence of HER2 mutations in ctDNA generally matched those in tumor tissues, and elevated ctDNA fractions were linked to poorer outcomes. Further research is necessary to validate the role of ctDNA in optimizing anti-HER2 therapy for HER2-mutated tumors.

Ferroptosis is a potential feature of neratinib-induced colonic injury and that targeting molecular machinery governing neratinib-induced ferroptosis may represent an attractive therapeutic approach to ameliorate symptoms of gut toxicity.

P1, N=20, Not yet recruiting, Baylor Research Institute | Initiation date: Nov 2023 --> Aug 2024

We observed Intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pre-treated.

P3, N=300, Recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University | Trial primary completion date: Feb 2024 --> Feb 2028

P2, N=460, Recruiting, Patrick Wen, MD | N=250 --> 460

P2, N=48, Recruiting, Ruth O'Regan | Trial completion date: May 2024 --> Oct 2024

P1, N=30, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.

P2, N=30, Recruiting, Vanderbilt-Ingram Cancer Center | Not yet recruiting --> Recruiting